1. Field of the Invention
The present invention relates generally to the production and purification of fluoromethyl 1,1,1,3,3,3-hexafluoroisopropyl ether (sevoflurane), which is used as an inhalation anesthetic.
2. Description of Related Art
There are several known methods for the production of sevoflurane, particularly by the reaction of formaldehyde (or a formaldehyde equivalent such as paraformaldehyde or trioxane), hydrogen fluoride (HF), and 1,1,1,3,3,3-hexafluoroisopropanol (HFIP). U.S. Pat. No. 4,250,334 describes a process in which HFIP is added to a mixture of a stoichiometric excess of paraformaldehyde and HF plus sufficient sulfuric acid to sequester most of the water formed in the reaction. WO 97/25303 describes a process for the production of sevoflurane in which essentially pure bis(fluoromethyl) ether (BFME) is allowed to react with HFIP and sulfuric acid. U.S. Pat. No. 6,469,219 ('219) describes a process in which HFIP and a formaldehyde equivalent are allowed to react with excess HF under distillative or extractive conditions in order to produce sevoflurane.
In all of these processes, unreacted HFIP may remain in the product mixture, as well as BFME, methyl hexafluoroisopropyl ether (MHFIP), polyethers containing the HFIP and formaldehyde moieties, and various other undesired species. These impurities must be removed from the crude sevoflurane product in order to obtain a pharmaceutically acceptable form of the material. For example, a pharmaceutically acceptable form of sevoflurane should contain less than about 20 ppm of HFIP.
Many impurities in crude sevoflurane product can be removed by distillation. HFIP, however, is difficult to distil from sevoflurane since the two molecules have similar boiling points and may form an azeotropic mixture. Simple washing of the crude sevoflurane product with water to remove HFIP has been reported, in US 2004/0124076 for example, to be inefficient, time consuming, and costly.
Thus, Example 1 of European Patent Application EP 703 450 describes a process for producing sevoflurane by heating a reaction mixture of sulfuric acid, hydrogen fluoride, and paraformaldehyde. The resulting crude product was extracted three times with water. As a result of prosecution of the corresponding U.S. application (resulting in issuance of U.S. Pat. No. 7,230,142), the mixture was later shown to contain about 4.7% HFIP. Such an amount is unacceptable for clinical grade sevoflurane.
WO 99/44978 and related U.S. Pat. No. 7,230,142 describe a process for the removal of HFIP from sevoflurane by performing aqueous base washes of crude sevoflurane. This process requires careful control of the amount of base used in proportion to the amount of HFIP present, as well as careful temperature control in order to avoid the conversion of some of the sevoflurane to sevoflurane compound A (1,1,1,3,3-pentafluoroisopropenyl fluoromethyl ether), a highly toxic and undesired side product. Prolonged processing with repeated sampling and analysis is required in order to ensure adequate removal of HFIP without formation of excess sevoflurane compound A. Thus, this approach has the disadvantages of complexity and added cost in the production process.
U.S. Pat. No. 7,230,142 also describes two comparative examples wherein a mixture of HFIP and sevoflurane is washed with pure water in an attempt to remove HFIP. In one comparative example, an initial amount of 10% HFIP in a mixture with sevoflurane was reduced to 3.4% HFIP by washing with water. In another comparative example, an initial amount of 0.25% HFIP in a mixture with sevoflurane was not reduced at all by washing with water.
WO 02/50005 and related US 2004/0124076 describe a process for purifying a crude sevoflurane product mixture by contacting a crude composition of sevoflurane and HFIP with a modifier to alter the vapor pressure of the ether and/or alcohol. The ether and alcohol then may be separated by distillation. The modifier is typically a compound which contains a group capable of bonding with or at least of donating electrons to HFIP, such as an amino group. The use of such a modifier adds cost and complexity to the production process since the modifier must be completely removed from both (i) the sevoflurane and (ii) the unreacted HFIP that is recycled back into the reaction phase. The modifier then must either be recycled or isolated for disposal. Odor issues are also of concern when amines or thiols are used as the modifier.
Middleton and Lindsey in the Journal of the American Chemical Society, 1964, 86: 4948-4952 have described azeotropes of fluorinated secondary alcohols, such as hexafluoroisopropanol, in which the normal boiling point is higher than the boiling point of the alcohol. Methods of breaking these azeotropes were also described, but applications of these azeotropes were not described.
International PCT application US2006/030046 of Halocarbon Products Corporation describes a process of purifying a crude sevoflurane product containing unacceptably high levels of HFIP. In this process, the crude sevoflurane product is combined with sufficient water to produce a multiphase mixture, the multiphase mixture is fractionally distilled, and substantially pure sevoflurane is removed from the fractionally distilling multiphase mixture. A disadvantage of this process is that the distillation may add to the cost and complexity of the process.
Other proposed methods of sevoflurane synthesis, such as that described in U.S. Pat. No. 6,100,434, avoid this difficult sevoflurane/hexafluoroisopropanol separation by using more complicated methods of synthesis.
What is still needed is a simple method for the efficient separation of sevoflurane and HFIP. Surprisingly, the inventors have discovered a simple, inexpensive, and convenient process for the purification of crude sevoflurane that results in purified sevoflurane.